The mechanisms responsible for mediating the secondary respiratory responses to acute and chronic hypoxia remain obscure. The primary reason for the obscurity is that more than one mechanism is involved; depending upon the mechanism activated either inhibition or stimulation of respiration can be produced. Although the classical chemical stimuli have received intensive research emphasis, it is now apparent that they alone do not explain all of the effects of hypoxia. The present studies take a different approach in attempting to elucidate these mechanisms. The long-range hypothesis of this proposal is that the secondary actions of hypoxia are due to interactions among neuronal networks and to effects on neurochemical substances which modulate the activity of neurons that control respiration. These mechanisms can be activated directly by hypoxia or indirectly by afferent input from the peripheral chemoreceptors. The proposed studies use phrenic nerve activity to represent ventilation, thereby allowing use of "open-loop" preparation that avoids negative chemical feedback associated with changes in ventilation. Specific aims are: 1) To determine in newborn and adult animals if the inhibitory effects of hypoxia on respiration emanate from the higher brain, 2) To study the role of the ventral medulla in mediating the respiratory responses to hypoxia, 3) To study the effect of hypoxia on the respiratory response to chemoreceptor, pulmonary mechanoreceptor and muscle test stimuli, 4) To study further the mechanism by which a brief exposure to severe hypoxia causes long-lasting inhibition of respiration in glomectomized cats, 5) To study the mechanism by which afferent input from carotid bodies cause long-lasting facilitation of respiration during chronic hypoxia, 6) To quantitate the role of the aortic bodies in the initial response to hypoxia, 7) To determine the effect of hypoxia on medullary ECF pH, 8) To examine the effect of hypoxia on spinal reflexes. The findings of these studies should lead to a better understanding of the central nervous system mechanisms involved in acute and chronic adaptation to hypoxia. The findings should also prove helpful in providing a better understanding of abnormalities associated with hypoxia that occur in clinical disease states and of potential ways to treat them.